MUC1 Expression in Colorectal Cancer is Associated with Malignant Clinicopathological Factors

This study aimed to evaluate the frequency, distribution, and corresponding histology of MUC1 expression in colorectal cancer and examine its association with clinicopathological factors. MUC1 expression was confirmed in 86 of 169 surgically resected colorectal cancers (51%), although the ratio of MUC1-positive cells was less than 5% in 33 cases (20%), 5-50% in 46 cases (27%), and greater than 50% in only 7 cases (4%). None or less than 5% of MUC1 expression cases were classified as L-group cancers (116 cases, 69%), while cancers showing higher than 5% expression were classified into the H-group (53 cases, 31%). Analysis of the intratumoral distribution of positive cells in the H-group cases showed MUC1 expression distributed predominantly in the upper layers in 3 cases (6%), in the lower layers in 18 cases (34%), and in all layers in 32 cases (60%). MUC1 expression was observed in various histomorphological cancer forms, but the most frequent expression was noted in the monolayer cuboidal (pancreatobiliary-type) neoplastic glands. Considering the relationship between MUC1 expression and clinicopathological factors, H-group cases demonstrated significantly larger lesions showing a greater number of ulcerated-type cancers, deeper invasion, poorer differentiation, higher frequency of budding, and higher rate of lymph node metastasis than L-group cancers. Furthermore, there was a difference of 10% between the H-group and L-group with regard to the frequency of relapse/tumor mortality three years after surgery. In colorectal cancer, MUC1 expression increases with progression of the tumor indicating that it is one of the useful indicators of malignancy and may facilitate appropriate treatment regimens; however, as its expression is heterogeneous and localized, it will be necessary to confirm the state of MUC1 expression by case

Functional Fv fragment of an antibody specific for CD28: Fv-mediated co-stimulation of T cells

AbstractThe most predominant co-stimulation pathway, which is critical for T cell activation and proliferation, is the CD28-B7 pathway. The anti-CD28 monoclonal antibody (mAb) also provides a co-stimulatory signal to T cells. In order to construct a functional Fv fragment (complex of VH and VL domains) of anti-CD28 antibody using a bacterial expression system, cDNA encoding the variable regions of immunoglobulin from 15E8 hybridoma cells was cloned and expressed in Escherichia coli. The Fv fragment was obtained as a soluble protein from the periplasmic fraction and showed a binding pattern similar to parental IgG. The Fv fragment induced proliferation of peripheral blood mononuclear cells in the presence of anti-CD3 or anti-CD2 mAb and enhanced anti-tumor activity of anti-MUC1×anti-CD3 bispecific antibody when tested with lymphokine-activated killer cells with T cell phenotype. Thus, the anti-CD28 Fv fragment will be promising not only for the study of co-stimulation, but also for cancer immunotherapy

Significance of Ki-67 Expression and Risk Category (St. Gallen 2007) in Elderly Breast Cancer Patients, with Emphasis on the Need for Postoperative Adjuvant Therapy

Breast cancer is increasing in the elderly. Although elderly breast cancer patients frequently receive less invasive therapy, its appropriateness is debatable. Ki-67 expression is a controversial prognostic factor and predictor of the efficacy of postoperative adjuvant therapy. This study investigated the value of the Ki-67 labeling index (LI) in elderly breast cancer patients, especially with respect to adjuvant therapy. This retrospective study investigated 82 primary breast cancer patients aged 70 years who underwent surgery between 1995 and 2005. Their clinicopathological findings were reviewed and their Ki-67 LIs were determined. The patients\u27 mean age was 78 years, the mean observation period was 53.8 months, and 60 patients (73.2%) underwent adjuvant therapy. The St. Gallen (2007) risk category and the Ki-67 LI (mean, 15.3%) were both significantly correlated with relapse and prognosis. In the 31 cases with a low Ki-67 LI (< 10%), 1 patient who underwent adjuvant treatment relapsed, but there were no deaths. Among the intermediate- and high-risk patients, Ki-67 was low in 15; 1 patient who underwent adjuvant treatment relapsed, but there were no deaths. For elderly breast cancer patients aged 70 years categorized low risk by St. Gallen (2007) or with a low Ki-67 LI, the risk of relapse and death appears to be low regardless of adjuvant therapy. Though further investigation is needed to determine a method of measuring the Ki-67 LI and determining a cut-off value, our findings suggest that the Ki-67 LI helps with the selection of adjuvant therapy in elderly patients

A Clinicopathological Study of Primary Small Intestinal Cancer with Emphasis on Cellular Characteristics

We examined the clinicopathological profiles and cellular characteristics of 10 cases of surgically resected primary small intestinal cancers (excluding duodenal cancers). Histological examination revealed nine adenocarcinomas and one sarcomatoid carcinoma. Invasion depth was subserosal in five cases, serosal in four cases and to the adjacent transverse colon in the remaining case. Metastasis was present in lymph node in seven cases, in distant organs in six, and in the peritoneum in seven cases. Of the 10 cases, 7 underwent postoperative chemotherapy, and 6 of the eight traceable patients died from the disease (mean period of survival: 386 days). Histomorphologically, eight of nine adenocarcinomas showed an intestinal phenotype (unclassifiable in the other) in the upper layer, while in the lower layer, there showed an intestinal phenotype and five a non-intestinal phenotyp. Immunohistochemistry revealed a mean positive rate in the upper/lower layers as follows: 93%/86% and 38%/29% by intestinal markers CDX2 and MUC2; 19%/28% and 13%/32% by pancreatobiliary markers CK7 and MUC1; and 4%/19% and 2%/9% by gastric markers MUC5AC and MUC6, respectively. Thus, the intestinal phenotype predominated in almost all small intestinal cancer in this study, although some showed a transformation to non-intestinal or hybrid phenotypes with tumor progression. Flexible management for the diversity and transformation of cellular characteristics is therefore recommended treating and diagnosing small intestinal cancers

Poly ADP-ribose Polymerase (PARP) Staining for Immunohistological Investigation of Primary Breast Cancer

Given that clinical trials of poly ADP-ribose polymerase (PARP) 1 inhibitors are underway, in the present study we investigated the prevalence of triple-negative breast cancer and PARP1 expression in patients with primary invasive breast cancer. Immunohistological studies plus PARP staining were performed on samples from 206 primary breast cancer patients undergoing surgery at Showa University Hospital between January 2010 and May 2011. Fifteen patients (7.3%) were found to have triple-negative breast cancer. Hormone receptor-positive patients were significantly more likely to be PARP1 negative. There were no PARP1-negative patients in the triple-negative group. However, there was no significant difference in the rate of PARP1 negativity between patients with triple-negative breast cancer and those with other breast cancer subtypes. There were no PARP1-negative patients in the triple-negative breast cancer group. Given that the effectiveness of PARP inhibitors has not been sufficiently established in clinical trials, a more in-depth analysis is required to determine the factors contributing to effective treatment. Future studies should include more subjects with triple-negative breast cancer and those with BRCA mutations

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Involvement of SIK3 in Glucose and Lipid Homeostasis in Mice

Salt-inducible kinase 3 (SIK3), an AMP-activated protein kinase-related kinase, is induced in the murine liver after the consumption of a diet rich in fat, sucrose, and cholesterol. To examine whether SIK3 can modulate glucose and lipid metabolism in the liver, we analyzed phenotypes of SIK3-deficent mice. Sik3−/− mice have a malnourished the phenotype (i.e., lipodystrophy, hypolipidemia, hypoglycemia, and hyper-insulin sensitivity) accompanied by cholestasis and cholelithiasis. The hypoglycemic and hyper-insulin-sensitive phenotypes may be due to reduced energy storage, which is represented by the low expression levels of mRNA for components of the fatty acid synthesis pathways in the liver. The biliary disorders in Sik3−/− mice are associated with the dysregulation of gene expression programs that respond to nutritional stresses and are probably regulated by nuclear receptors. Retinoic acid plays a role in cholesterol and bile acid homeostasis, wheras ALDH1a which produces retinoic acid, is expressed at low levels in Sik3−/− mice. Lipid metabolism disorders in Sik3−/− mice are ameliorated by the treatment with 9-cis-retinoic acid. In conclusion, SIK3 is a novel energy regulator that modulates cholesterol and bile acid metabolism by coupling with retinoid metabolism, and may alter the size of energy storage in mice